The serotonin system governs many higher order neural functions that control the interaction and perception of an individual with their internal and external environment. Optimally, the serotonin system renders an individual stress-resilient and adaptable, with positive effect and capable of functioning at a high level. Inadequacy of the serotonin system is observed in individuals with depression and anxiety disorders. The results of the last project period strongly indicate that the ovarian steroids, estrogen (E) and progesterone (P), facilitate serotonin synthesis and serotonin neural activity in monkeys. In addition, preliminary data from Affymetrix array analysis indicates that ovarian steroids potentially protect serotonin neurons from neurotoxic or programmed death, and that they act on genes that are involved in neural remodeling and plasticity. This proposal seeks to further the hypothesis that ovarian steroids protect serotonin neurons from death and that E and P promote neuronal plasticity and intracellular trafficking in the midbrain raphe. Aim 1 will further the hypothesis that E and P are neuroprotective of serotonin neurons by characterizing (at gene, protein and functional levels) the localization and hormonal regulation of two death genes, KMO (kynurenin mono- oxygenase) and JNK-1 (c-jun N-terminal kinase), and of a novel transcript, CART (cocaine and amphetamine regulated transcript), that are markedly suppressed by E, with or without P. Aim 2 will further the hypothesis that P has unique anti-stress/anti-cytokine actions in serotonin neurons by characterizing the localization and hormonal regulation of two genes, E2F1, a pivotal transcription factor, and the GABA-Aa3 subunit. Aim 3 will test the hypothesis that ovarian hormones promote serotonin neuron survival by applying design-based stereology to count serotonin neurons in semi-free ranging macaques. Behavioral correlates of serotonin cell number will be sought. In addition, TUNEL and caspase 3 assays will be applied to the same animals to determine the functional consequences of Aims 1 and 2. Aim 4 will confirm additional genes that promote neuronal plasticity and intracellular trafficking in the raphe, extend data mining of the current array results and probe new rhesus microarrays with laser captured serotonin neurons. Altogether, we will show that ovarian steroids support serotonin neuron survival and we will provide pivotal underlying genomic mechanisms.